Sleep and memory formation are both complex neurobiological "emergent" processes of considerable interest. The relationship between them has been a contentious issue-is sleep really necessary for memory formation (the sleep/memory hypothesis)? In this proposal, we will try to answer in a definitive manner this age-old question. Both of these processes are also commonly disrupted in neurological, neurodegenerative, and psychiatric dysfunctions. Whether "improving" one or the other can have broad-spectrum benefits is not clear. It is also unknown if enhancing one process will improve the other. This proposal has three broad parts. In the first, we have identified a gene that is involved in regulating sleep. Mild overexpression of this gene alters sleep, and enhances memory formation. Disrupting the gene has extreme effects on sleep. The tests (increase gene, test sleep and memory;disrupt gene, test sleep and memory) will be repeated using a second inducible system to validate current data. We will also use the gene to try to overcome sleep deprivation's harmful effects on memory formation. In the second part, we test the importance of particular "times of night" in memory formation. Finally, we test the functional and molecular interaction between a newly identified gene that interacts with our sleep-regulating gene. Taken together, this data should provide strong support for the sleep/memory hypothesis. This work has immediate medical impact, since almost all patients diagnosed with neurodegenerative and psychiatric diseases have sleep and cognitive problems. PUBLIC HEALTH RELEVANCE: Most, if not all, patients who suffer from neurodegenerative and psychiatric dysfunctions have problems with both sleep and cognition. Recently (Pallier et al. J Neurosci, 27, 7869-78, 2007), it was shown that a mouse model for Huntington's Disease has sleep and cognition problems. When these mice were treated for 4 weeks with a sleep-promoting drug, it partially reversed their cognitive deficits. This proposal addresses the problem of whether normal sleep contributes to memory formation. Eventually, this work will help identify pharmacological reagents that are countermeasures for sleep-related problems, cognitive deficits, and perhaps, both.